The field of epigenetics encompasses the process of changes in gene expression that involve covalent modification of either residues in histone proteins or of DNA bases. These changes can be essential for the pathogenesis of a number of disease states, including cancer. We focus on a particular class of modifiers for histone proteins, histone methyltransferases, which are known to methylate lysine and arginine residues. These epigenetic modifiers have been recognized as significant contributors to both normal development and disease states. The lysine methyltransferase DOT1L belongs to this class of enzymes and has been linked to leukemogenesis. We demonstrate how the combination of in silico structure-based drug design and small-molecule library screening has aided in the identification of potential inhibitors of DOT1L. Our study is focused on identifying potential inhibitors of DOT1L. To accomplish this task, we have optimized analogues of the S-adenosyl methionine (SAM) cofactor in silico. In addition, we have synthesized relevant compounds to this study such as the close SAM analogue Aza-SAM. These syntheses will aid in assay development and will eventually allow testing of potential DOT1L inhibitors in biological assays.

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